Adhesive compositions and products

ABSTRACT

Chlorhexidine gluconate-containing adhesives have dispersed therein solid chlorhexidiene particles which will pass through a 125 μm sieve and at least about 30% of the total volume of particles has a size of not less than 5 μm. The adhesive may be a vinyl ether adhesive and may be coated upon a backing layer such as a hydrophilic polyurethane to produce products suitable for use as wound dressings, IV dressing or incise drapes. The chlorhexidine gluconate may be obtained as a freeze-dried solid and added directly, in suspension, to the adhesive mass without further milling.

This invention relates to adhesive compositions and to adhesiveproducts. More particularly, the invention relates to medicated adhesivecompositions and to products coated therewith.

Adhesive products containing a releasable medicament in the adhesive areknown. The advantage of having a medicament, such as an anti-bacterialagent, in the adhesive is that the medicament is delivered to the sitefor release and use when the adhesive is applied eg. as part of a wounddressing. By providing a vehicle from which such medicaments asanti-bacterial agents can be released in a sustained manner, the areacan be maintained free from bacterial infection. A known medicatedadhesive product containing an antibacterial agent is sold under thetrade name "OpSite CH" By T. J. Smith and Nephew Limited. Theantibacterial incorporated into the adhesive layer is chlorhexidineacetate.

Chlorhexidine gluconate is also a well known antibacterial agent.However, because it is a extremely hygroscopic material its use islimited and in many applications it can only be used as a 20% aqueoussolution, which is commercially available. In our researches we havefound that it has only been possible to use gluconate solutions inadhesive formulations in amounts not exceeding about 3% by weight ofchlorhexidine gluconate since at levels much above this the tackproperties of the adhesive are adversely affected.

We have now found it possible to prepare chlorhexidinegluconate-containing adhesive compositions having higher levels ofanti-bacterial activity and acceptable adhesive values then has beenhitherto available.

Thus in accordance with the invention, there is provided an adhesivecomposition, suitable for medical applications, comprising an adhesivehaving dispersed therein solid particles of chlorhexidine gluconate,wherein said particles have a particle size of less than 125 μm and atleast about 30% by volume of the particles have a particle size of notless than 5 μm.

Particles used in the invention which have a particle size of less than125 μm are particles which will pass through a 125 μm mesh screen.

The solid form of chlorhexidine gluconate may be obtained byfreeze-drying aqueous solutions of the gluconate, eg the commerciallyavailable 20% aqueous solution. The particle size of the freeze driedmaterial is usually of a suitable size that the material requires nofurther comminution prior to incorporation into the adhesive mass.

The adhesives used in the invention may be any of those medicallyacceptable adhesives which are compatable with the gluconate. Inparticular the adhesive material should not contain groupings, such asfree acid groups, which will react with the gluconate and thus render itunavailable for release. Suitably, the adhesive is one which ishydrophilic in nature.

Apt adhesives for use in the adhesive composition of the invention mayinclude acrylic adhesives and adhesives based on polyvinyl ethers. Apreferred acrylic adhesive is described in European Patent PublicationNo. 35399. A typical polyvinyl ether adhesive composition suitable foruse in the present invention is that described as adhesive composition Ain UK Patent specification No. 1280631.

The amount of chlorhexidine gluconate that is present in the adhesivecan range up to 10% by weight of the weight of the composition withoutadversely affecting the tack of the adhesive. Thus amounts ofchlorhexidine gluconate can be included which would exhibit bactericidalproperties as well as bacteriostatic properties. Hitherto it has notbeen possible to include more than about 3% by weight chlorhexidinegluconate, as an aqueous solution, before the adhesive surface becomesdeadened. At such low levels the anti-bacterial activity is restrictedto that of bacteriostatic activity and with such adhesive compositionslittle or no bactericidal activity is observed.

We have also found that, on a weight for weight basis, adhesives basedon solid gluconate have superior anti-bacterial properties than thoseadhesives based on chlorhexidine gluconate in solution. Effectivebactericidal activity can be achieved at concentrations of from 2-3% byweight.

In accordance with a further aspect of the invention there is provided aprocess for the production of an adhesive composition which comprisesadmixing particles of chlorhexidine gluconate with a medicallyacceptable adhesive wherein the particles have a particle size of lessthan 125 μm and wherein at least about 30% by volume of the particleshave a particle size of not less than 5 μm.

In a preferred embodiment of the process of the invention, freeze driedparticles of chlorhexidine gluconate are dispersed in a liquid which isa non-solvent for the gluconate but a solvent for the adhesive. Theliquid may suitably be a non-polar liquid. Thus for a composition baseon a polyvinyl ether adhesive, a suitable solvent for the adhesive,which is a non-solvent for chlorhexidine gluconate is petroleum ether,commercially available is SBP2.

Dispersion of the particles can be achieved by conventional mixingtechniques such as high shear mixing. After formation of the dispersionwith the as-produced freeze dried chlorhexidine gluconate, thedispersion may be filtered through a suitably sized mesh screen and theparticles caught on the screen recycled to the mixing zone.

We have found that by the choice of relatively large sizes of particles,good adhesion values can be retained and yet good release properties ofthe antibacterial can be achieved. If any significant comminution of theas-produced freeze dried product takes place, the adhesive properties ofthe composition are adversely affected.

The adhesive compositions of the invention are suitable for use in themanufacture of adhesive products such as wound dressings, intra-venousaccess site dressings (IV dressings) and surgical drapes.

Thus in accordance with another aspect of the present invention there isprovided an adhesive product comprising a backing layer having coatingthereon of a medically acceptable adhesive having dispersed thereinsolid particles of chlorhexidine gluconate, wherein said particles havea particle size of less than 125 μm and at least about 30% by volume ofthe particles have a particle size of not less than 5 μm.

The backing layer employed in the adhesive products of the presentinvention are desirably capable of conforming to the body contours whenapplied to the skin and should be flexible enough to move with the bodywithout becoming detached. Suitable flexible backing materials includeknitted, woven or non-woven fabrics, nets, microporous films such asplasticised polyvinyl chloride films, polymer blend films containingvoids, polymeric films, including thermoplastic polyurethane andhydrophilic polyurethane, elastomeric polyesters, styrene-butadieneblock copolymers such as Kraton (Trade mark) thermoplastic rubbers.

Favored materials which may be used at the backing layer in the adhesiveproduct of the present invention include films of hydrophilic polymers.Apt hydrophilic polymers include hydrophilic polyurethanes, polyvinylpyrrolidone, polyvinyl alcohol and cellulosic derivatives.

A favored hydrophilic polymer is a hydrophilic polyurethane. Suitablehydrophilic polyurethanes include those having the composition andprepared by the process described in British Patent No. 2093190B. Themost suitable hydrophilic polyurethanes are those which contain from 5to 50% by weight of water when hydrated, more suitably from 10 to 40% byweight of water and which have a thickness when present in a dressing offrom 25 to 120 μm, more suitably 30 to 60 μm. A preferred film ofhydrophilic polyurethane has a water content when hydrated of 20 to 30%for example 25% and a thickness of up to 50 μm for example 30 μm.

A favored flexible backing material is a microporous plasticisedpolyvinyl chloride film formed by the process disclosed in BritishPatent No. 884232. preferred microporous plasticised polyvinyl chloridefilms have a thickness of from 100 to 300 μm typically between 150 μmand 250 μm for example about 200 μm.

A further favored backing layer is a film of thermoplastic polyurethaneincluding the linear polyester polyurethanes or polyether polyurethanesknown as Estanes (Trade mark). Such polyurethanes are used as films from15 to 75 μm in thickness, more favorably 20 to 35 μm in thickness forexample about 25 μm or 30 μm.

The adhesive layer may vary in thickness depending upon the type of skinlesion, wound or other similar use the dressing is to be put, that isthinner layers up to about 5 mm may be used on non-exuding wounds or ondressings for use at intravenous sites while thicker layers for exampleup to 25 mm may be used on exuding wounds where the absorptiveproperties of the adhesive may be advantageously used.

The adhesive products of the present invention may be prepared bycasting the backing layer from a solution of the appropriate polymer ata suitable concentration onto a silicone release paper and removing thesolvent to give a film of the required thickness. A film of the adhesivecomposition at the required thickness is prepared and the two filmsbrought together and adhered to each other to form a laminate,preferably without the use of any further adhesives. Handles may beapplied at any convenient stage during the production of the dressing.Release coated protectors may be placed over the adhesive layer orlayers and the laminate cut into dressings of the appropriate size forexample 5 cm×5 cm, 7.5 cm×7.5 cm, 8 cm×8 cm, 10 cm×10 cm, 5 cm×10 cm and10 cm×20 cm. The adhesive products, when used as wound dressings, forexample, may be packaged in a bacteria-proof and water-proof pouch andbe sterilized by conventional methods such as irradiation and ethyleneoxide.

In use the sterile dressing is removed from the pouch, the protectorremoved from the adhesive surface of the dressing and the dressing isapplied to the wound.

Dressings in accordance with the invention may be used as a dressing forwounds caused by physical or surgical trauma, burns, ulcers and thelike, as a surgical drape, as dressing for intravenous access sites andany dressing for which long term attachment to the skin may be required.

In a further aspect therefore the present invention provides a method oftreating a wound on an animal body by applying to the wound an adhesivedressing as hereinbefore described.

By a suitable choice of adhesive and/or backing layer, the adhesiveproducts of the invention may be rendered impervious to water, yet willallow moisture vapor to pass therethrough. The rate at which moisturevapor passes through the dressing is the moisture vapor transmissionrate (MVTR). The MVTR can be determined either with water in contactwith the dressing (the `inverted MVTR`) or in contact with water vaporalone (`upright MVTR`).

A suitable method of determining the upright moisture vapor transmissionrate of the dressing of this invention is as follows. Discs of materialunder test are clamped over Payne Permeability Cups (flanged metal cups)using sealing rings and screw clamps. The exposed surface area of thetest sample may be conveniently 10 cm². Each cup contains approximately10 ml of distilled water. After weighing the cups are placed in a fanassisted electric oven maintained at 37±1° C. The relative humiditywithin the oven is maintained at 10% by placing 1 Kg of anhydrous 3-8mesh calcium chloride on the floor of the oven. The cups are removedafter 24 hours, allowed to cool for 20 minutes and re-weighed. The MVTRof the test material is calculated from the weight loss expressed inunits of grams of weight per square meter per 24 hours.

A suitable method of determining the inverted moisture vaportransmission rate of the dressing of this invention is as follows. Themethod described above is employed except that the Payne Cups areinverted in the oven so that the water within the cups is in contactwith the test material and in this case with the adhesive.

Aptly adhesive products in accordance with the present invention willhave MVTR's in excess of 300 gm⁻² and preferably greater than 500 gm⁻²,suitably more than 1200 gm⁻². Inverted MVTR's are preferably greaterthan upright MVTR's and are desirably greater than about 1200 gm⁻².

In a preferred aspect therefore the present invention provides anadhesive product in the form of a wound dressing which includes backingmaterial comprising a hydrophilic polyurethane and a continuous layer ofpressure sensitive adhesive comprising an adhesive composition inaccordance with the invention and the product has a moisture vaportransmission rate of between 1400 and 1600 gm⁻² 24h⁻² at 37° C. and 100to 10% relative humidity difference when the adhesive is in contact withmoisture vapor.

The present invention will be illustrated by the following example.

A slurry was prepared of freeze dried chlorhexidine gluconate inpetroleum ether (SBP2) using a high shear mixer. The concentration ofthe chlorhexidine gluconate was 12.5% w/w.

A portion of the slurry was then pumped to a SUSSMEYER Bead Millcomprising a 1.5 liter stainless steel shell filled with up to 99%volume of 1 mm diameter lead-free glass beads. The milled slurry waspassed through a 125 μm sieve to remove any unmilled gluconate and anybroken glass particles. Particle size distribution analysis showed thatalmost all the particles were below 16 μm with 48% in the range 2-4 μm.

A further portion of the slurry was passed directly through the 125 μmmesh sieve, without milling. Particle size analysis of this portionshowed that, again most of the particles were below 16 μm. However anumber of particles were found in the 16 to 100 μm range.

A vinyl ether adhesive was made as described for Composition A in UKPatent Specification No. 1280631.

To one part of the adhesive was added the screened slurry of milledchlorhexidine gluconate to a concentration of 5.3% by weight and toanother part of the adhesive was added the screened slurry of theunmilled gluconate, again at a chlorhexidine gluconate concentration of5.3%.

A third part of the adhesive was retained as a control and contained noadded chlorhexidine gluconate.

Each of the three adhesives were cast onto a 25 μm thick polyurethanefilm at a coating weight of 30 gm⁻²

Samples of each of the coated films were then subjected to ethyleneoxide sterilisation and thereafter tested for microbiological activityby the IOBAN zone diffusion test against Staphloccocus aureus 10788 incomparison with non-sterilized samples of each coated film. Thebacterial counts were made initially (0 mins) and after the lapse of 5minutes. The results of the IOBAN tests are reported below.

    ______________________________________                                                         Mean Log.sub.10                                                                        Count/ml                                                      Sterilising                                                                            Sample Time (mins)                                         Medicament  condition  0          5                                           ______________________________________                                        None (Control)         5.78 ± 0.01                                                                           5.80 ± 0.02                              Un-milled   Non-Sterile                                                                              5.89 ± 0.07                                                                           2.12 ± 0.05                              Milled                 5.83 ± 0.03                                                                           2.09 ± 0.53                              None (Control)         5.93 ± 0.08                                                                           5.88 ± 0.06                              Un-milled              5.90 ± 0.10                                                                           2.18 ± 0.80                              Milled                 5.76 ± 0.18                                                                           2.77 ± 0.01                              ______________________________________                                    

I claim:
 1. An adhesive composition, suitable for medical applications,comprising an adhesive having dispersed therein 2-10% by weight, basedon the weight of the composition, of solid particles of chlorhexidinegluconate, wherein said particles have a particle size of less than 125μm and at least about 30% by volume of the particles have a particlesize of not less than 5 μm.
 2. A composition as claimed in claim 1wherein the adhesive is an acrylic or polyvinyl ether based adhesive. 3.An adhesive product comprising a backing layer having coated thereon anadhesive composition as defined in any one of the preceding claims.
 4. Aproduct as claimed in claim 3 which has a moisture vapor transmissionrate of at least 300 gm⁻² 24h⁻¹ at 37° C. and at a 100% to 10% relativehumidity difference when in contact with moisture vapor.
 5. A product asclaimed in claim 3 in which the backing layer is a flexible materialselected from knitted, woven or non-woven fabrics, nets, microporous orcontinuous synthetic polymer films.
 6. A product as claimed in claim 5wherein the backing layer is a synthetic polymer film comprising apolyurethane.
 7. A product as claimed in claim 6 wherein thepolyurethane comprises a hydrophilic polyurethane which contains from 5to 50% by weight of water when hydrated.
 8. A product as claimed in anyof the claims 4 to 7 in the form of a wound dressing for non-exudingwounds and having an adhesive thickness of up to about 5 mm.
 9. Aproduct as claimed in any one of the claims 4 to 7 in the form of awound dressing for exuding wounds and having an adhesive thickness of upto 25 mm.
 10. A dressing pack containing a dressing as claimed in claim9 in sterile form and contained within a bacteria and water proof pouch.11. A method of treating a wound on an animal by applying to the woundan adhesive dressing as claimed in claim 9.